DESCRIPTION (applicant's abstract): Many individuals suffer from disorders (e.g., Cushing's syndrome, depression) involving high circulating stress-related hormones, glucocorticoids. Furthermore, millions of individuals take prescription glucocorticoids, which are immunodepressants effective in treating asthma, autoimmune disorders, and organ transplant rejection. Chronically high plasma glucocorticoids are associated with reduced hippocampal volume in humans and increased susceptibility to damage. Similarly they cause cognitive deficits. The effects of exercise in brain and muscle are opposite in direction to those of sustained glucocorticoids. Furthermore, exercise has been shown to protect the brain from damage (e.g., ischemia), and reduces symptoms of depression. An animal model provides the opportunity to perform the invasive experiments critical for a precise understanding of the damage caused by glucocorticoids and the beneficial effects of exercise. My hypothesis is that exercise will prevent or attenuate damage and behavioral deficits normally associated with stress-related hormones. To address this hypothesis, Specific Aim 1 seeks to develop a precise understanding of hippocampal damage caused by corticosterone, the predominant stress-related hormone in rats. Specific aim #2 seeks to determine whether or not exercise can prevent corticosterone-mediated cognitive deficits. Specific Aim #3 will test whether or not exercise can prevent or reduce corticosterone-related damage to the brain. The anatomical analyses will use the most rigorous methods available. The results from these studies will provide critical information about the importance of exercise prior to and during corticosterone treatment. Furthermore, they will have implications for the reduction of corticosterone-mediated damage in diseases associated with high glucocorticoids. The results may also elucidate a potential mechanism through with exercise reduces the symptoms of depression, a disease precipitated by stress.